RESUMO
Although clinical signs and symptoms of giant cell arteritis improve promptly after starting glucocorticoid therapy, reports have suggested that the vascular inflammation may persist. To assess the duration and quality of histopathologic changes in treated patients, we prospectively obtained second temporal artery biopsies in patients treated for 3 to 12 months after their first diagnostic biopsy. Forty patients (28 women, 12 men, median age 77 years) agreed to have a second temporal artery biopsy randomly assigned to 3, 6, 9, or 12 months subsequent to the first. Clinical and laboratory evaluation of the patient cohort revealed a typical rapid response and continued suppression of clinical manifestations as a result of glucocorticoid treatment. Histopathologic findings, evaluated in a blinded manner by a cardiovascular pathologist, showed unequivocal findings of vasculitis in 7/10 patients with second temporal artery biopsy at 3 months, 9/12 at 6 months, 4/9 at 9 months, and 4/9 at 12 months. Lymphocytes were present in all positive initial biopsies and remained the dominant cell population in chronically treated patients. Granulomatous inflammation decreased in a time-dependent manner from 78 to 100% at initial biopsy to 50% at 9 months and 25% at 12 months. The increased medial fibrosis noted in the second biopsies (60 vs 33% in primary temporal artery biopsies) suggested that the finding may represent a chronic finding in arteritis. In summary, the response to glucocorticoids in giant cell arteritis was frequently discordant. Clinical manifestations were readily suppressed, but vascular changes were gradual and often incomplete.
Assuntos
Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/patologia , Glucocorticoides/uso terapêutico , Prednisona/uso terapêutico , Artérias Temporais/efeitos dos fármacos , Artérias Temporais/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Fibrose , Arterite de Células Gigantes/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Distribuição Aleatória , Artérias Temporais/imunologia , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Cranial nerve schwannomas are radiologically characterized by nodular cranial nerve enhancement on magnetic resonance imaging (MRI). Schwannomas typically present with gradually progressive symptoms, but isolated reports have suggested that schwannomas may cause fluctuating symptoms as well. METHODS: This is a report of ten cases of presumed cranial nerve schwannoma that presented with transient or recurring ocular motor nerve deficits. RESULTS: Schwannomas of the third, fourth, and fifth nerves resulted in fluctuating deficits of all 3 ocular motor nerves. Persistent nodular cranial nerve enhancement was present on sequential MRI studies. Several episodes of transient oculomotor (III) deficts were associated with headaches, mimicking ophthalmoplegic migraine. CONCLUSIONS: Cranial nerve schwannomas may result in relapsing and remitting cranial nerve symptoms.
Assuntos
Neoplasias dos Nervos Cranianos/complicações , Neurilemoma/complicações , Doenças do Nervo Oculomotor/diagnóstico , Doenças do Nervo Oculomotor/etiologia , Adulto , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The acromelic dysplasias comprise short stature, hands and feet, and stiff joints. Three disorders are ascribed to this group, namely Weill-Marchesani syndrome, geleophysic dysplasia, and acromicric dysplasia, although similar in phenotype, can be distinguished clinically. Weill-Marchesani syndrome, on the basis of microspherophakia and ectopia lentis; geleophysic dysplasia by progressive cardiac valvular thickening, tracheal stenosis, and/or bronchopulmonary insufficiency, often leading to early death. Microspherophakia has not been reported previously in geleophysic dysplasia. Mutations in FBN1, ADAMTS10, or ADAMTS17 cause Weill-Marchesani syndrome by disrupting the microfibrillar environment, while geleophysic dysplasia is associated with enhanced TGF-ß signaling mediated through mutations in FBN1 or ADAMTSL2. We studied a 35-year-old woman with geleophysic dysplasia, with short stature, small hands and feet, limitation of joint mobility, mild skin thickening, cardiac valvular disease, restrictive pulmonary disease, and microspherophakia. Sequencing of ADAMTSL2 demonstrated two changes: IVS8-2A>G consistent with a disease-causing mutation, and IVS14-7G>A with potential to generate a new splice acceptor site and result in aberrant mRNA processing. The unaffected mother carries only the IVS8-2A>G transition providing evidence that the two changes are in trans-configuration in our patient.
Assuntos
Doenças do Desenvolvimento Ósseo/fisiopatologia , Diagnóstico Diferencial , Deformidades Congênitas dos Membros/fisiopatologia , Síndrome de Weill-Marchesani/fisiopatologia , Proteínas ADAM/genética , Proteínas ADAMTS , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adulto , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Nanismo/genética , Nanismo/fisiopatologia , Feminino , Fibrilina-1 , Fibrilinas , Humanos , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , Proteínas dos Microfilamentos/genética , Patologia Molecular , Mutação Puntual , Síndrome de Weill-Marchesani/diagnóstico , Síndrome de Weill-Marchesani/genéticaRESUMO
BACKGROUND: Giant cell arteritis is a granulomatous vasculitis of the aorta and its branches that causes blindness, stroke, and aortic aneurysm. CD4 T cells are key pathogenic regulators, instructed by vessel wall dendritic cells to differentiate into vasculitic T cells. The unique pathways driving this dendritic cell-T-cell interaction are incompletely understood, but may provide novel therapeutic targets for a disease in which the only established therapy is long-term treatment with high doses of corticosteroids. METHODS AND RESULTS: Immunohistochemical and gene expression analyses of giant cell arteritis-affected temporal arteries revealed abundant expression of the NOTCH receptor and its ligands, Jagged1 and Delta1. Cleavage of the NOTCH intracellular domain in wall-infiltrating T cells indicated ongoing NOTCH pathway activation in large-vessel vasculitis. NOTCH activation did not occur in small-vessel vasculitis affecting branches of the vasa vasorum tree. We devised 2 strategies to block NOTCH pathway activation: γ-secretase inhibitor treatment, preventing nuclear translocation of the NOTCH intracellular domain, and competing for receptor-ligand interactions through excess soluble ligand, Jagged1-Fc. In a humanized mouse model, NOTCH pathway disruption had strong immunosuppressive effects, inhibiting T-cell activation in the early and established phases of vascular inflammation. NOTCH inhibition was particularly effective in downregulating Th17 responses, but also markedly suppressed Th1 responses. CONCLUSIONS: Blocking NOTCH signaling depleted T cells from the vascular infiltrates, implicating NOTCH- NOTCH ligand interactions in regulating T-cell retention and survival in vessel wall inflammation. Modulating the NOTCH signaling cascade emerges as a promising new strategy for immunosuppressive therapy of large-vessel vasculitis.
Assuntos
Proteínas de Ligação ao Cálcio , Dipeptídeos/farmacologia , Arterite de Células Gigantes , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas de Membrana/metabolismo , Receptor Notch1 , Transdução de Sinais/efeitos dos fármacos , Transferência Adotiva , Animais , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Células Dendríticas/imunologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interferon gama/metabolismo , Interleucina-17/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Proteína Jagged-1 , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Camundongos , Camundongos SCID , Receptor Notch1/antagonistas & inibidores , Receptor Notch1/genética , Receptor Notch1/metabolismo , Proteínas Serrate-Jagged , Transdução de Sinais/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Quimeras de Transplante , Transplante HeterólogoRESUMO
BACKGROUND: In giant cell arteritis (GCA), vasculitic damage of the aorta and its branches is combined with a syndrome of intense systemic inflammation. Therapeutically, glucocorticoids remain the gold standard because they promptly and effectively suppress acute manifestations; however, they fail to eradicate vessel wall infiltrates. The effects of glucocorticoids on the systemic and vascular components of GCA are not understood. METHODS AND RESULTS: The immunoprofile of untreated and glucocorticoid-treated GCA was examined in peripheral blood and temporal artery biopsies with protein quantification assays, flow cytometry, quantitative real-time polymerase chain reaction, and immunohistochemistry. Plasma interferon-gamma and interleukin (IL)-17 and frequencies of interferon-gamma-producing and IL-17-producing T cells were markedly elevated before therapy. Glucocorticoid treatment suppressed the Th17 but not the Th1 arm in the blood and the vascular lesions. Analysis of monocytes/macrophages in the circulation and in temporal arteries revealed glucocorticoid-mediated suppression of Th17-promoting cytokines (IL-1beta, IL-6, and IL-23) but sparing of Th1-promoting cytokines (IL-12). In human artery-severe combined immunodeficiency mouse chimeras, in which patient-derived T cells cause inflammation of engrafted human temporal arteries, glucocorticoids were similarly selective in inhibiting Th17 cells and leaving Th1 cells unaffected. CONCLUSIONS: Two pathogenic pathways mediated by Th17 and Th1 cells contribute to the systemic and vascular manifestations of GCA. IL-17-producing Th17 cells are sensitive to glucocorticoid-mediated suppression, but interferon-gamma-producing Th1 responses persist in treated patients. Targeting steroid-resistant Th1 responses will be necessary to resolve chronic smoldering vasculitis. Monitoring Th17 and Th1 frequencies can aid in assessing disease activity in GCA.
Assuntos
Arterite de Células Gigantes/imunologia , Interleucina-17/imunologia , Células Th1/imunologia , Animais , Quimera/sangue , Quimera/imunologia , Modelos Animais de Doenças , Arterite de Células Gigantes/sangue , Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/patologia , Glucocorticoides/farmacologia , Humanos , Interferon gama/sangue , Interferon gama/imunologia , Interleucina-17/sangue , CamundongosRESUMO
PURPOSE OF REVIEW: Granuloma formation in giant cell arteritis (GCA) emphasizes the role of adaptive immunity and highlights the role of antigen-specific T cells. Recent data demonstrate that at least two separate lineages of CD4 T cells participate in vascular inflammation, providing an important clue that multiple disease instigators may initiate pathogenic immunity. RECENT FINDING: IFN-γ-producing Th1 cells and IL-17-producing Th17 cells have been implicated in GCA. Patients with biopsy-positive GCA underwent two consecutive temporal artery biopsies, one prior to therapy and one while on corticosteroids. In untreated patients, Th1 and Th17 cells co-existed in the vascular lesions. Following therapy, Th17 cells were essentially lost, whereas Th1 cells persisted almost unaffected. In the peripheral blood of untreated patients Th17 frequencies were increased eight-fold, but normalized with therapy. Blood Th1 cells were doubled in frequency, independent of therapy. Corticosteroids functioned by selectively suppressing IL-1ß, IL-6 and IL-23-releasing antigen-presenting cells (APCs), disrupting induction of Th17 cells. SUMMARY: At least two distinct CD4 T-cell subsets promote vascular inflammation in GCA. In early disease, APCs promote differentiation of Th17 as well as Th1 cells. Chronic disease is characterized by persistent Th1-inducing signals, independent of IL-17-mediated inflammation. More than one disease instigator may trigger APCs to induce multiple T-cell lineages. Cocktails of therapies will be needed for appropriate disease control.
Assuntos
Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/patologia , Células Th1/imunologia , Células Th1/patologia , Células Th17/imunologia , Células Th17/patologia , Imunidade Adaptativa , Corticosteroides/uso terapêutico , Animais , Células Apresentadoras de Antígenos/imunologia , Arterite de Células Gigantes/tratamento farmacológico , Humanos , Interferon gama/biossíntese , Interleucina-17/biossíntese , Camundongos , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Receptores Toll-Like/imunologiaRESUMO
Large vessel vasculitides, such as Takayasu arteritis and giant cell arteritis, affect vital arteries and cause clinical complications by either luminal occlusion or vessel wall destruction. Inflammatory infiltrates, often with granulomatous arrangements, are distributed as a panarteritis throughout all of the artery's wall layers or cluster in the adventitia as a perivasculitis. Factors determining the architecture and compartmentalization of vasculitis are unknown. Human macrovessels are populated by indigenous dendritic cells (DCs) positioned in the adventitia. Herein, we report that these vascular DCs sense bacterial pathogens and regulate the patterning of the emerging arteritis. In human temporal artery-SCID chimeras, lipopolysaccharides stimulating Toll-like receptor (TLR)4 and flagellin stimulating TLR5 trigger vascular DCs and induce T-cell recruitment and activation. However, the architecture of the evolving inflammation is ligand-specific; TLR4 ligands cause transmural panarteritis and TLR5 ligands promote adventitial perivasculitis. Underlying mechanisms involve selective recruitment of functional T cell subsets. Specifically, TLR4-mediated DC stimulation markedly enhances production of the chemokine CCL20, biasing recruitment toward CCL20-responsive CCR6(+) T cells. In adoptive transfer experiments, CCR6(+) T cells produce an arteritis pattern with media-invasive T cells damaging vascular smooth muscle cells. Also, CCR6(+) T cells dominate the vasculitic infiltrates in patients with panarteritic giant cell arteritis. Thus, depending on the original danger signal, vascular DCs edit the emerging immune response by differentially recruiting specialized T effector cells and direct the disease process toward distinct types of vasculitis.
Assuntos
Células Dendríticas/imunologia , Arterite de Células Gigantes/imunologia , Ativação Linfocitária , Subpopulações de Linfócitos T/imunologia , Artérias Temporais/imunologia , Receptor 4 Toll-Like/metabolismo , Receptor 5 Toll-Like/metabolismo , Adjuvantes Imunológicos/farmacologia , Transferência Adotiva , Animais , Células Cultivadas , Quimiocina CCL20/metabolismo , Quimiotaxia de Leucócito , Células Dendríticas/efeitos dos fármacos , Modelos Animais de Doenças , Arterite de Células Gigantes/patologia , Humanos , Ligantes , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos SCID , Músculo Liso Vascular/imunologia , Músculo Liso Vascular/patologia , Receptores CCR6/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/transplante , Artérias Temporais/efeitos dos fármacos , Artérias Temporais/patologia , Artérias Temporais/transplante , Técnicas de Cultura de TecidosRESUMO
BACKGROUND: Inflammatory vasculopathies, ranging from the vasculitides (Takayasu arteritis, giant cell arteritis, and polyarteritis nodosa) to atherosclerosis, display remarkable target tissue tropisms for selected vascular beds. Molecular mechanisms directing wall inflammation to restricted anatomic sites within the vascular tree are not understood. We have examined the ability of 6 different human macrovessels (aorta and subclavian, carotid, mesenteric, iliac, and temporal arteries) to initiate innate and adaptive immune responses by comparing pathogen-sensing and T-cell-stimulatory capacities. METHODS AND RESULTS: Gene expression analysis for pathogen-sensing Toll-like receptors (TLRs) 1 to 9 showed vessel-specific profiles, with TLR2 and TLR4 ubiquitously present, TLR7 and TLR9 infrequent, and TLR1, TLR3, TLR5, TLR6, and TLR8 expressed in selective patterns. Experiments with vessel walls stripped of the intimal or adventitial layer identified dendritic cells at the media-adventitia junction as the dominant pathogen sensors. In human artery-severe combined immunodeficiency (SCID) mouse chimeras, adoptively transferred human T cells initiated vessel wall inflammation if wall-embedded dendritic cells were conditioned with TLR ligands. Wall-infiltrating T cells displayed vessel-specific activation profiles with differential production of CD40L, lymphotoxin-alpha, and interferon-gamma. Vascular bed-specific TLR fingerprints were functionally relevant, as exemplified by differential responsiveness of iliac and subclavian vessels to TLR5 but not TLR4 ligands. CONCLUSIONS: Populated by indigenous dendritic cells, medium and large human arteries have immune-sensing and T-cell-stimulatory functions. Each vessel in the macrovascular tree exhibits a distinct TLR profile and supports selective T-cell responses, imposing vessel-specific risk for inflammatory vasculopathies.
Assuntos
Artérias/fisiologia , Perfilação da Expressão Gênica , Receptores Toll-Like/fisiologia , Artérias/anatomia & histologia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Cultura de Órgãos , Receptores Toll-Like/classificaçãoRESUMO
PURPOSE: To delineate the disease course and prognosis of patients with mass lesions of the fourth nerve presumed to be schwannomas. DESIGN: Nonrandomized retrospective case series. PARTICIPANTS: Thirty-seven consecutive cases of presumed trochlear nerve schwannoma from 9 tertiary university neuro-ophthalmology centers. METHODS: Cases were collected, and their clinical characteristics on presentation and follow-up are described. Inclusion criteria were brain magnetic resonance imaging (MRI) with a lesion suggestive of a schwannoma along the course of the fourth nerve. Exclusion criteria were other causes of fourth nerve palsy, such as congenital, traumatic or microvascular; normal (or lack of) initial brain MRI; lack of adequate clinical information; and disappearance of the lesion on subsequent follow-up brain MRI. MAIN OUTCOME MEASURES: Demographics of patients, presence of neurofibromatosis, symptoms on presentation, vertical deviation, lesion size (on presentation and follow-up), length of follow-up, and outcomes of treatment for lesions or diplopia. RESULTS: Seven patients were excluded and of the 30 patients included in our series, patients were predominantly male (77%) with a mean age of 51 years (range 9-102 years). In contrast with prior case reports, almost all of our cases had a fourth nerve palsy on presentation (29/30), often isolated. Mean follow-up was 3.1 years (range 0.2 months to 11.1 years). There was no significant difference between initial and follow-up lesion size (4.4 vs. 5 mm) for patients who did not receive treatment of lesions (P = 0.36). Only 3 patients underwent neurosurgical resection and an additional patient received gamma-knife radiotherapy. The majority of patients (24/30) did not pursue strabismus surgery for vertical diplopia. CONCLUSIONS: Patients with isolated fourth nerve palsy and small lesions of the fourth nerve have a good prognosis and should be followed with serial MRI scans without neurosurgical intervention unless they develop signs of brain stem compression. Most patients with diplopia and benign fourth nerve lesions typical of trochlear nerve schwannoma can adapt with either prism spectacles or no treatment at all, although strabismus surgery can be successful.
Assuntos
Neoplasias dos Nervos Cranianos/patologia , Neurilemoma/patologia , Doenças do Nervo Troclear/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Neoplasias dos Nervos Cranianos/terapia , Diplopia/diagnóstico , Óculos , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neurilemoma/terapia , Prognóstico , Radiocirurgia , Estudos Retrospectivos , Doenças do Nervo Troclear/terapiaRESUMO
A 24-year-old woman with systemic lupus erythematosus presented with a 1-year history of painless vision loss in the right eye. Examination was notable for a bitemporal hemianopia. Brain imaging revealed multiple contrast enhancing dural masses, including one along the planum sphenoidale. She underwent excisional biopsy for a presumed diagnosis of multiple meningiomas. Five years later, she developed worsening vision in the left eye, hypesthesia in the V1 distribution, and oculomotor nerve palsy. Repeat imaging showed an enhancing mass in the cavernous sinus and orbital apex. Biopsy demonstrated a lymphoplasmacyte rich infiltrate in dense extracellular material. She was diagnosed with lupus-induced hypertrophic pachymeningitis and started on immunosuppressive therapy. On further worsening of symptoms, her initial biopsy was reexamined and revealed a kappa light chain restricted B-cell and plasmacyte population. This led to the final diagnosis of central nervous system extranodal marginal zone lymphoma.
Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Biomarcadores Tumorais/metabolismo , Neoplasias do Sistema Nervoso Central/metabolismo , Diagnóstico Diferencial , Feminino , Humanos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/diagnóstico , Linfoma de Zona Marginal Tipo Células B/metabolismo , Imageamento por Ressonância Magnética , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Meningite/diagnóstico , Transtornos da Visão/diagnóstico , Adulto JovemRESUMO
PURPOSE: To report a case of bilateral optic disk edema in a patient taking oprelvekin for radioimmunotherapy-induced thrombocytopenia. DESIGN: Observational case report. METHODS: A 38-year-old man with a history of relapsed non-Hodgkins follicular lymphoma complained of bilateral loss of vision following oprelvekin therapy for thrombocytopenia. RESULTS: Funduscopic examination demonstrated bilateral optic disk edema with exudates inferotemporal to the right nerve. The results of magnetic resonance imaging of the brain and orbits and lumbar puncture were normal. The disk edema resolved with discontinuation of oprelvekin therapy. CONCLUSIONS: Oprelvekin therapy may be associated with bilateral optic disk edema. This has been shown to be reversible in a primate model.
Assuntos
Antineoplásicos/efeitos adversos , Interleucina-11/efeitos adversos , Papiledema/induzido quimicamente , Proteínas Recombinantes/efeitos adversos , Adulto , Humanos , Linfoma Folicular/radioterapia , Masculino , Radioimunoterapia/efeitos adversos , Trombocitopenia/tratamento farmacológico , Trombocitopenia/etiologiaRESUMO
OBJECTIVE: To identify clinical findings in patients with suspected giant cell arteritis (GCA) that may help clinicians decide when to initiate glucocorticoid therapy. PATIENTS AND METHODS: Medical diagnostic codes and surgical indexing were used to identify all patients who had temporal artery biopsy at the Mayo Clinic in Rochester, Minn, between January 1, 1988, and December 31, 1997. Patient medical records were abstracted for pertinent clinical data, glucocorticoid use, and final diagnoses. Sensitivities, specificities, predictive values, and likelihood ratios were calculated for the association of the various clinical findings and the presence of a positive biopsy result. Graphic and arithmetic models were constructed to predict positive temporal artery biopsy results. RESULTS: During the 10-year interval, 1113 patients had temporal artery biopsy. The results were positive for GCA in 373 patients (33.5%) and negative in 740 (665%). Twenty percent of all patients were taking glucocorticoids at the time of biopsy. The presence of jaw claudication had a positive predictive value of 78. Combinations of jaw claudication with new headache, scalp tenderness, and decreased vision had still higher values. Positive likelihood ratios in patients with these combinations and in those with diplopia were greater than 3. A normal erythrocyte sedi-mentation rate in patients not taking corticosteroids provided a high negative likelihood ratio of 40. An arithmetic equation provided the probability of a positive biopsy result on a continuous scale using 6 variables identified by logistic regression. Patients with a greater than 80% chance of a positive biopsy result and those with less than a 10% chance were identified. CONCLUSION: Positive predictive values, likelihood ratios, and an arithmetic formula identify patients who have an increased or decreased chance of a positive temporal artery biopsy result. Use of these methods to determine early initiation of glucocorticoid therapy before temporal artery biopsy or deferral until after biopsy may help reduce both vascular complications of GCA and adverse effects of corticosteroids.
Assuntos
Anti-Inflamatórios/administração & dosagem , Biópsia/métodos , Arterite de Células Gigantes , Glucocorticoides/administração & dosagem , Seleção de Pacientes , Prednisona/administração & dosagem , Artérias Temporais , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Biópsia/normas , Sedimentação Sanguínea , Esquema de Medicação , Feminino , Arterite de Células Gigantes/complicações , Arterite de Células Gigantes/diagnóstico , Arterite de Células Gigantes/tratamento farmacológico , Cefaleia/etiologia , Humanos , Claudicação Intermitente/etiologia , Arcada Osseodentária/irrigação sanguínea , Funções Verossimilhança , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Sensibilidade e Especificidade , Fatores de Tempo , Transtornos da Visão/etiologiaRESUMO
PURPOSE: To describe a treatable form of nystagmus. METHODS: Two patients recently evaluated at the Mayo Clinic had experienced various forms of oscillopsia, imbalance, and worsening symptoms with a Valsalva maneuver. Close inspection of the eye revealed a subtle rotatory nystagmus that was synchronous with the heartbeat. RESULTS: The two patients had surgical treatment for dehiscence of the superior semicircular canal; postoperatively, their symptoms completely resolved. This is a relatively newly discovered condition that has not been described on either slit-lamp or ophthalmoscopic examination. The cause is related to a dehiscence of the superior semicircular canal that permits communication of variable pressures between the intracranial cavity and the perilymphatic spaces of the semicircular canal. CONCLUSION: Being aware of this unusual form of nystagmus may permit physicians to diagnose it--one of the few treatable forms of nystagmus.
Assuntos
Contração Miocárdica , Nistagmo Patológico/fisiopatologia , Nistagmo Patológico/cirurgia , Humanos , Doenças do Labirinto/complicações , Doenças do Labirinto/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Nistagmo Patológico/etiologia , Canais Semicirculares/diagnóstico por imagem , Canais Semicirculares/cirurgia , Tomografia Computadorizada por Raios XRESUMO
A 57-year-old man developed acute bilateral vision loss clinically consistent with bilateral optic neuritis. Within 1 month of diagnosis, he developed progressive and severe neurologic dysfunction, and repeat MRI demonstrated enhancement of the optic chiasm and optic tracts, as well as a large enhancing lesion within the right parieto-occipital lobe. Stereotactic-guided brain biopsy demonstrated demyelination consistent with multiple sclerosis. A diagnosis of fulminant multiple sclerosis was made. The patient died within 2 months of diagnosis. Multiple sclerosis and a fulminant subtype known as Marburg disease are discussed.
Assuntos
Glucocorticoides/uso terapêutico , Esclerose Múltipla/diagnóstico , Quiasma Óptico/patologia , Neurite Óptica/diagnóstico , Cegueira/diagnóstico , Evolução Fatal , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Neurite Óptica/tratamento farmacológico , Técnicas Estereotáxicas , Vias Visuais/patologiaRESUMO
OPA1 is highly expressed in retina and optic nerve. OPA1 mutations were first identified in patients with non-syndromic autosomal dominant optic atrophy. Recently, OPA1 mutations were detected in a multisystemic disorder which has optic atrophy as the core clinical feature and multiple mitochondrial DNA (mtDNA) deletions in muscle. We report a patient with a multisystemic disorder and multiple muscle mtDNA deletions, carrying an in-frame deletion in OPA1 in the absence of optic atrophy. This patient provides evidence that optic atrophy is not the main clinical manifestation of OPA1-related disorders. OPA1 analysis should be considered in mitochondrial disorders despite the lack of optic atrophy.
Assuntos
DNA Mitocondrial/genética , GTP Fosfo-Hidrolases/genética , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Atrofia Óptica/patologia , Deleção de Sequência , Feminino , Humanos , Pessoa de Meia-Idade , Músculo Esquelético/patologiaRESUMO
PURPOSE OF REVIEW: Inflammatory vasculopathies, spanning from atherosclerosis to vasculitides, are driven by innate and adaptive immune responses. Instructed by antigen-presenting cells, T cells have unsurpassed skills to orchestrate protective and pathogenic immunity. Pro-inflammatory and anti-inflammatory T cells regulate master pathogenic pathways, providing a framework for novel immunotherapeutic strategies. RECENT FINDINGS: The multilayered wall of macrovessels creates a unique tissue niche; professional antigen-presenting cells, specifically dendritic cells, are superior in triggering and maintaining T-cell responses in this tissue milieu. Plaque-residing dendritic cells sense pathogen-derived motifs and edit inflammatory responses. T cells respond to antigen but antigen-nonspecific factors setting cellular response thresholds may be equally important. Dysregulated signal transduction pathways emerge as highly relevant in biasing T cells toward hyperresponsiveness. In the inflamed atheroma and in arteritic lesions, pathogenic T cells coordinate multiple injury pathways. Besides inducing tissue-damaging macrophage functions, they directly inflict cellular injury within the arterial wall. Distinctively, selected T cells induce smooth muscle cell apoptosis, most prominently by upregulating the death-receptor ligand TRAIL. SUMMARY: Innate sentinels, specifically dendritic cells, populate normal arteries, intramural vasculitic lesions, and the inflamed atheroma. They sense microbial motifs and instruct T cells toward pro-inflammatory and tissue-destructive effector functions. Microenvironmental factors imposed by the unique structure of the arterial wall appear to be highly conserved across disease entities, modulating inflammation in atherosclerosis and arteritis.
Assuntos
Arterite/imunologia , Aterosclerose/imunologia , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Arterite/patologia , Aterosclerose/patologia , Citocinas/metabolismo , Humanos , Modelos Biológicos , Transdução de Sinais/imunologia , Linfócitos T/metabolismoRESUMO
PURPOSE: To define the kinetics and mechanisms of frank arteritis onset in patients with giant cell arteritis. METHODS: Cytokines were analyzed from tissue of a patient before and after the development of arteritis. RESULTS: A temporal artery biopsy specimen from a patient with giant cell arteritis showed no pathologic changes on microscopic examination, but there was evidence of early tissue activation of inflammatory markers. A specimen from the contralateral artery 12 days later had high levels of IL-18 transcripts and abundant transcripts for CCL19. Also, CD83 and IL-1 were present, confirming that the vascular dendritic cells had fully matured. This second biopsy specimen showed floridly positive giant cell arteritis on histopathologic examination. CONCLUSIONS: Partial activation of vascular dendritic cells is typically seen in patients with polymyalgia rheumatica in whom no inflammatory infiltrates are seen on histomorphologic examination. Dendritic cells become activated at an early stage of arteritis, beginning the pathologically evident arteritis, and are fully matured in microscopically florid arteritis.
Assuntos
Arterite de Células Gigantes/sangue , Idoso , Vasos Coronários/fisiopatologia , Citocinas/sangue , Arterite de Células Gigantes/complicações , Arterite de Células Gigantes/genética , Arterite de Células Gigantes/fisiopatologia , Humanos , Incidência , Inflamação/patologia , Inflamação/fisiopatologia , Interleucina-18/genética , Masculino , Polimialgia Reumática/complicações , Polimialgia Reumática/epidemiologia , Artérias Temporais/patologia , Artérias Temporais/fisiopatologia , Transcrição GênicaRESUMO
BACKGROUND: Ophthalmoscopy of the fundus in a patient with head tremor is facilitated by image stability, whereas such observation of a patient with nystagmus is made difficult by image movement. Why does this occur? METHODS: We offer an explanation of these observations and derive mathematical proofs for both direct and indirect ophthalmoscopes in various states of ametropia. RESULTS: By means of image displacement calculations, we have created a graphical display of refractive error versus image displacement, showing zero displacement in emmetropia in head tremor and exaggerated displacement during nystagmus, regardless of the refractive status of the eye. CONCLUSIONS: Simple optics and a mathematical proof explain the clinical observations. The image stability in the patient with head tremor and the image instability in an eye with nystagmus are the consequences of the optical system of the eye.
Assuntos
Movimentos da Cabeça , Nistagmo Patológico/fisiopatologia , Oftalmoscopia/métodos , Retina/patologia , Tremor/fisiopatologia , Fundo de Olho , Humanos , Matemática , ObservaçãoRESUMO
OBJECTIVE: Glucocorticoid (GC) therapy for giant cell arteritis (GCA) is effective but requires prolonged administration, resulting in adverse side effects. The goal of the current study was to test the hypothesis that induction treatment with high-dose pulse intravenous (IV) methylprednisolone permits a shorter course of therapy. METHODS: Twenty-seven patients with biopsy-proven GCA were enrolled in a randomized, double-blind, placebo-controlled study to receive IV methylprednisolone (15 mg/kg of ideal body weight/day) or IV saline for 3 consecutive days. All patients were started on 40 mg/day prednisone and followed the same tapering schedule as long as disease activity was controlled. The numbers of patients with disease in remission after 36, 52, and 78 weeks of treatment and taking Assuntos
Arterite de Células Gigantes/tratamento farmacológico
, Glucocorticoides/administração & dosagem
, Glucocorticoides/uso terapêutico
, Metilprednisolona/administração & dosagem
, Metilprednisolona/uso terapêutico
, Prednisona/administração & dosagem
, Prednisona/uso terapêutico
, Administração Oral
, Idoso
, Idoso de 80 Anos ou mais
, Relação Dose-Resposta a Droga
, Método Duplo-Cego
, Feminino
, Arterite de Células Gigantes/fisiopatologia
, Glucocorticoides/efeitos adversos
, Humanos
, Infusões Intravenosas
, Masculino
, Metilprednisolona/efeitos adversos
, Pessoa de Meia-Idade
, Prednisona/efeitos adversos
, Estudos Prospectivos
, Pulsoterapia
, Indução de Remissão/métodos
, Prevenção Secundária
, Resultado do Tratamento
RESUMO
OBJECTIVE: In giant cell arteritis (GCA), inflammatory lesions typically produce interferon-gamma(IFNgamma)-- and nuclear factor kappaB (NF-kappaB)-dependent monokines. Corticosteroids influence disease activity by repressing NF-kappaB-dependent genes but have only marginal effects on IFNgamma. The current study explored whether acetylsalicylic acid (ASA) had cytokine-repressing activity in GCA and could function as a steroid-sparing agent. METHODS: Temporal artery-severe combined immunodeficiency (SCID) mouse chimeras were created by engrafting inflamed temporal arteries into SCID mice. Chimeras were treated with ASA, indomethacin, or dexamethasone for 3 weeks. Temporal artery grafts were harvested and cytokine message was semiquantified by polymerase chain reaction-enzyme-linked immunosorbent assay. The ability of dexamethasone and ASA to suppress IFNgamma and interleukin-1beta (IL-1beta) messenger RNA and protein production was also tested in vitro using T cell clones and monocytes derived from patients with GCA. Drug-induced effects on the transcription factors NF-kappaB and activator protein 1 (AP-1) were assessed by electrophoretic mobility shift assays (EMSAs). RESULTS: At clinically relevant doses, 20-100 mg/kg, ASA was a highly effective inhibitor of cytokine transcription in temporal arteries. While dexamethasone preferentially targeted NF-kappaB-regulated monokines, ASA acted predominantly by suppressing IFNgamma. Indomethacin failed to reduce tissue IFNgamma transcription, which therefore excluded the inhibition of cyclooxygenases as a critical mechanism. IFNgamma production by T cell clones was highly sensitive to ASA-mediated suppression, whereas IL-1beta production by lipopolysaccharide-stimulated monocytes responded primarily to dexamethasone. The combination of ASA and dexamethasone had synergistic effects. EMSAs demonstrated that ASA interfered with the formation of AP-1, whereas dexamethasone suppressed the nuclear translocation of NF-kappaB. CONCLUSION: The results of this study provide evidence of the complementary action of ASA and corticosteroids in suppressing proinflammatory cytokines in the vascular lesions of GCA.